The advent of Highly Active Anti-Retroviral Therapy (HAART) has led to a significant increase in life expectancy for human immunodeficiency virus (HIV)-infected individuals, prompting attention toward conditions such as hepatitis C virus (HCV) coinfection, which may adversely affect the lifespan and quality of life of HIV-infected persons. A significant number of individuals in the United States are infected with both HCV and HIV: 60%-90% of hemophiliacs and 50%-90% of injection drug users. In addition, a growing number of reports indicate that accelerated progression of liver fibrosis and increased rates of liver failure are found in HCV/HIV coinfection compared to those infected only with HCV. This rapid progression of liver disease has been found to correlate with lower peripheral blood CD4+ T cell counts, suggesting a link between CD4+ T cells and liver fibrosis progression. The overall goal of this proposal is to better understand the pathogenesis of HCV coinfection with HIV by investigating the relationship between liver fibrosis, intrahepatic HCV replication, and the quantity and function of HCV-specific intrahepatic CD4+ T cells, including their ability to secrete cytokines that promote fibrosis. Finally, we will test the hypotheses that HCV/HIV coinfected subjects treated with HAART will demonstrate improved HCV-specific CD4+ T cell function that is not fibrogenic, and is sequestered to the liver.